Risk factors for vertebral fracture in rheumatoid arthritis patients using biological disease-modifying anti-rheumatic drugs (cases over 5 years): An observational study

While biological disease-modifying anti-rheumatic drugs (bDMARDs) are considered beneficial for preventing osteoporosis and bone fracture, it is unclear whether bone loss is involved in the development of vertebral fracture, and few reports have examined the factors related to vertebral fracture in rheumatoid arthritis (RA) patients using bDMARDs. This study aims to identify factors influencing vertebral fracture in RA patients treated with bDMARDs. We retrospectively examined the records of 129 RA patients treated with bDMARDs for over 5 years. The lumbar spine and femoral bone mineral density, Disease Activity Score-28-C-Reactive Protein (DAS28-CRP) value, Simplified Disease Activity Index (SDAI), and modified Health Assessment Questionnaire (mHAQ) score were evaluated. The frequency of new vertebral fracture during the study and their risk factors were investigated. A comparison between the fracture group and the nonfracture group was performed. Multivariate analysis was performed using logistic regression analysis to detect risk factors for new vertebral fracture. The number of patients with new vertebral fracture during follow-up was 15 (11.6%) of the 129 patients in the study. Age and mHAQ score were significantly higher and lumbar spine and femoral neck bone mineral density were significantly lower in the fracture group than the nonfracture group. The risk factors for new vertebral fracture during the disease course were older age and higher mHAQ score indicating no remission over the 5 years of follow-up. In this study, there was no significant difference in disease indices such as the DAS28-CRP value and the SDAI between the fracture and nonfracture groups, suggesting an effective control of RA with bDMARDs. However, age and the mHAQ score, an index of RA dysfunction, were significantly higher in the fracture group. These results suggest that improving functional impairment may be important to prevent vertebral fracture in patients using bDMARDs.


Introduction
Rheumatoid arthritis (RA) is a chronic, systemic inflammatory disorder characterized by joint inflammation and destruction.Recent advances have broadened the spectrum of treatment options for RA, notably with the introduction of biological disease-modifying anti-rheumatic drugs (bDMARDs).
Treatment with bDMARDs not only induces rapid remission but also decreases radiological progression and disability. [1]here is emerging evidence suggesting that biologics might positively influence bone metabolism and bone remodeling. [2]chieving clinical and structural remission, as well as functional remission, is the primary goal of RA treatment.The modified Health Assessment Questionnaire (mHAQ, with a remission HT and HT contributed equally to this study.

The authors have no funding and conflicts of interest to disclose.
The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.Supplemental Digital Content is available for this article.criterion of ≤0.5) serves as a widely used tool for evaluating this aspect. [3]The mHAQ, which comprises 8 questions, provides insights comparable to those obtained from the 20 questions in the HAQ. [1]Both HAQ and mHAQ are effective for screening RA patients for physical function. [2]tudies have shown that RA patients treated with bDMARDs experience femoral bone loss, which is associated with higher steroid use and shorter disease duration. [4]Additionally, risk factors for having a femoral neck bone mineral density (BMD) below 70% of the young adult mean (YAM) include a low Geriatric Nutritional Risk Index (GNRI) as a nutritional marker and female sex. [5]However, the role of bone loss in vertebral fractures among RA patients treated with bDMARDs remains unclear, with limited research on the risk factors for vertebral fracture development in this group.
This study aimed to evaluate risk factors for vertebral fracture in RA patients treated with bDMARDs.

Materials and methods
This research has been approved by the IRB of the authors' affiliated institutions.This research was executed in accordance with the Helsinki Declaration of 1975, as revised in 2008.All subjects gave their informed consent for inclusion before participating in the study.

Demographic and disease-related data
Demographic and clinical data were collected from the medical records of 1178 patients with RA who were followed up for more than 5 years at our institution between 2011 and 2014.Overall, 376 of the 1178 patients were treated with bDMARDs.These data included several key parameters: sex, age, disease duration, and estimated glomerular filtration rate (eGFR) (mL/ min/1.73m 2 ).Additionally, we noted the average prescribed dose of methylprednisolone and the GNRI.For assessing RA disease activity, we used both the Disease Activity Score-28-C-Reactive Protein (DAS28-CRP), and the Simplified Disease Activity Index (SDAI).The mHAQ score was used to measure physical function.Finally, we collected data on serum CRP levels (mg/dL) and BMD at the lumbar spine and femoral neck (g/ cm 2 ).After 1 year, assessments of bone mass and nutrition were repeated to evaluate for improvements.
After 5 years, any vertebral fractures were evaluated by standing thoracolumbar spine radiographs, and new vertebral fractures were noted.Furthermore, the mHAQ was readministered.Vertebral fracture was defined as a grade 1 or higher fracture according to the semiquantitative (SQ) grading method as performed by a spine surgeon accredited by the Japanese Society for Spine Surgery and Related Research and an orthopedic specialist.The fracture group was defined as those patients with new vertebral fractures during follow-up, and the nonfracture group was defined as those patients without new vertebral fractures.In the fracture group, patients were prescribed corsets, but none underwent surgical intervention.

Dual-energy X-ray absorptiometry measurements
BMD was examined using a Discovery DXA system (Hologic, Waltham, MA, USA) between December 2011 and December 2014.The Japanese Society for Bone and Mineral Research recommends diagnosing of primary osteoporosis when BMD, expressed as a percentage of the YAM, falls below 70%.All patients diagnosed with osteoporosis received treatment for osteoporosis.One year following the initial staging, we reexamined the BMD in the lumbar spine and femoral neck.

Statistical analysis
Parameters were compared with the Wilcoxon test, Fisher exact test, and multivariate logistic regression analysis to determine risk factors for vertebral fracture.A stepwise procedure was used with the inclusion of variables that had a significance level of P < .05.The bivariate correlation analysis was performed for the correlation of variables.P < .05 was considered statistically significant.The JMP software program (version 16; SAS Institute, Cary, NC, USA) was used for statistical analysis.

Patients' demographic and clinical characteristics
The flowchart of this study is shown in Figure 1.The demographic and clinical characteristics of the 129 patients who underwent DXA scanning of the femoral neck and lumbar spine are shown in Table 1.
Among the 129 patients, approximately 85% were female, with a median age was 60 years.The lumbar and femoral percentages of the YAM were 86% and 76%, respectively, and the GNRI was 105.9, indicating good nutritional status.The DAS28-CRP value of the patients indicated remission, and the SDAI showed low activity (Table 1).

Comparison of demographic and clinical characteristics between the fracture and nonfracture groups
A total of 129 patients were on biologics for RA and were followed up for more than 5 years.New vertebral fractures occurred in 15 patients (11.6%) during the 5 years of RA treatment, with 10 of these fractures located in the thoracolumbar transition region.About 1 patient had SQ grade 1, 9 had SQ grade 2, and 5 had SQ grade 3 fractures.Comparative analysis revealed that the new vertebral fracture group had significantly higher ages and mHAQ scores, along with lower BMD in the femur and lumbar spine (Table 2).There were negative correlations between the BMD and YAM in the femoral neck and the disease duration (Supplemental Table 1, http://links.lww.com/MD/N68).There was no correlation between age and the mHAQ score, and there was no difference in the incidence of new vertebral fractures between types of bDMARDs.Old vertebral fractures were not a risk factor for new vertebral fractures.In the nonfracture group, the mHAQ score indicated that the patients remained in remission over the 5 years of follow-up (Table 3).

Risk factors for new vertebral fracture in RA patients
Multivariate logistic regression analysis showed that the risk factors for new vertebral fracture during the disease course were older age and an mHAQ score indicating no remission over the 5 years (Table 4).

Discussion
Limited research has examined the risk factors for vertebral fracture in RA patients treated with bDMARDs.This study aimed to identify such risk factors.We observed that new vertebral fractures were more likely to occur in older patients and less likely in those whose mHAQ score suggested remission.Notably, a high mHAQ score emerged as a significant risk factor for vertebral fractures in RA patients under bDMARDs therapy, even in cases of low RA activity.
The median DAS28-CRP value in RA patients treated with bDMARDs was 2.5, and the SDAI was 5.8, indicating low disease activity.Despite remaining in a low disease activity status, 11.6% of these patients showed a BMD ≤ 70% YAM in the lumbar spine.El Maghraoui et al reported that the prevalence of vertebral fracture was increased in patients with higher DAS28 scores. [6]RA is caused by inflammatory cytokines that lead to bone destruction and loss of bone mass. [7]Recent studies have shown that RA can be alleviated by bDMARDs.bDMARDs significantly improve RA symptoms, function, and remission rates in patients with prior treatment failure with methotrexate or conventional disease-modifying anti-rheumatic drugs (cDMARDs). [8]Van der Heijde et al [9] found that the use of bDMARDs led to improved physical function in patients with RA.Notably, low physical ability is associated with an increased risk of vertebral fracture. [10]In this study, bDMARDs resulted in remission based on the DAS28 value and low activity according to the SDAI, and the mHAQ score was high in the vertebral fracture group.
It has been reported that the mHAQ score is substantially higher in RA patients with new vertebral fractures. [11]Therefore, it is essential to prevent vertebral fractures to maintain the functional status of RA patients. [11]However, the report by Omata et al does not mention the type of RA medication used to achieve this. [11]In this study, in which bDMARDs were used by all patients, vertebral fractures occurred in 15 (11.6%) who were almost asymptomatic, averaging 1.3 mg/d prednisolone, suggesting that bDMARDs controlled their symptoms.Another group also showed that an mHAQ score >1.5 is correlated with bone loss in the proximal femur. [12]In this study, the median mHAQ score was 0.5; an mHAQ score of 0.5 or less is considered to indicate functional remission, [3] suggesting that low activities of daily living (ADLs) are likely to cause fracture even if RA activity is suppressed.
Dirven et al [13] reported that disease activity over time was higher in patients with vertebral fracture.This may be because of high levels of pro-inflammatory cytokines such as TNF-α and IL-6 in patients with high RA activity.Ghazi et al reported that the prevalence of vertebral fracture was inversely related to the use of steroids, [14] and Dirven et al [13] claimed no association between vertebral fracture and steroid use.In this study, steroids were not a risk factor for vertebral fracture because RA was controlled well.Takahashi et al found that the class and duration of biologics therapy were not significantly different in the BMD < 70% of femoral YAM and BMD ≥ 70% of femoral YAM groups. [15]n addition to influencing disease activity, biologics may prevent bone loss via a direct effect on bone metabolism.It is well recognized that TNF-α induces differentiation of osteoclast precursors through synergistic action with RANKL. [16]Shin et al did not find a significant difference in the risk of fracture  between TNF initiators and abatacept or tocilizumab among RA patients. [17]Our data showed no significant differences among the different bDMARDs in the incidence of vertebral fracture in RA patients.It has been reported that risk factors for the least significant lumbar spine and femoral neck reduction were high-dose methylprednisolone use and short disease duration, respectively. [4]However, another study reported that a longer RA disease duration is significantly related to the loss of BMD in the femoral neck and total femur. [18]Our findings showed negative correlations between the BMD and YAM in the femoral neck and the disease duration.A recent study has suggested that bDMARDs have a protective effect on bone loss compared to cDMARDs. [19]On the other hand, another report did not show any significant difference in vertebral fractures between bDMARD users and non-users. [20]In RA patients with relatively controlled inflammation, considerations other than bone loss may be necessary to prevent vertebral fractures.
The low GNRI, used here as a nutritional index, was a risk factor for bone loss at the femoral neck in bDMARD patients.Complementary nutritional therapies might improve RA activity and osteoporosis in RA patients who have undergone treatment with bDMARDs. [5]In this study, we tracked changes in the GNRI and bone mass; however, there was no association between improved nutrition and bone mass (femoral neck) and new vertebral fractures, suggesting that nutritional status may be an indicator of RA activity.
Patients who have had RA for a longer duration may be more likely to experience remission of the inflammatory state.Some people have a high mHAQ score even when their RA disease is in remission.It has been reported that abdominal trunk muscle weakness is a significant risk factor associated with osteoporotic vertebral fracture in the lower thoracic or lumbar spine. [21]Among RA patients who achieve disease control with bDMARDs, vertebral fractures may be prevented by maintaining ADLs through rehabilitation and other means.
Our study has several limitations.First, being a singlecenter cohort study, it may have been subjected to selection bias.Future research should involve a multicenter approach to confirm our findings.Second, we were unable to assess the dietary habits of patients in their home environments.Third, our study also did not incorporate nutritional interventions.Future studies should aim for a more comprehensive determination of variables and patient samples to accurately identify crucial risk factors.Fourth, there is a possibility that we missed patients with RA who were followed up for more than 5 years but may have transferred to other hospitals or dropped out of the study.

Conclusion
In patients with RA using bDMARDs, age and the mHAQ score, an index of RA dysfunction, were significantly higher in   the fracture group despite the of bDMARDs in controlling RA.These results suggest that improving functional impairment may be important to prevent vertebral fracture in patients using bDMARDs.

Table 1
Patient demographic data.

Table 2
Comparison of baseline data between fracture and nonfracture groups.

Table 3
Involvement of new vertebral fractures with types of bDMARDs and patient parameters.

Table 4
Multivariate logistic regression analysis of risk factors related to new vertebral fracture.